Process for producing N1 -(Dihydroxyalkyl)-5-substituted uracils

ABSTRACT

A process for producing N 1  -(dihydroxyalkyl)-5-substituted uracils of the formula: ##SPC1## 
     Wherein 
     R 1  is hydrogen, methyl, a trihalomethyl, a halogen, 
     R 2  is 1,4-dihydroxybutyl-2,1,4-dihydroxypentyl-2,2,5-dihydroxypentyl-1, 
     Characterized by reducing N 1  -(butyrolactone)uracils of the formula: ##SPC2## 
     Wherein 
     R 1  is hydrogen, methyl, a trihalomethyl, a halogen, 
     A is: ##SPC3## 
     With an alkali metal boron hydride in an aqueous or aquo-alcoholic solution at a temperature ranging from 15° to 50°C.

The present invention relates to a process for producing nucleoside analogues and, more specifically, to a process for producing N₁ -(dihydroxyalkyl)-5-substituted uracils corresponding to the generic formula: ##SPC4##

Wherein

R₁ is hydrogen, methyl, a trihalomethyl or a halogen;

R₂ is 1,4-dihydroxybutyl-2, 1,4-dihydroxypentyl-2, 2,5-dihydroxypentyl-1.

Said compounds are analogues of pyrimidine-nucleosides, wherein a sugar residue is replaced by a dihydroxyalkyl group. Such compounds are particularly interesting as possible inhibitors of nucleic exchange and may be useful for the production of analogues of mono-, oligo-nucleotides and nucleic acids.

Known in the art is a process for producing N₁ -(2,3-dihydroxypropyl-1)-uracil by alkylation of uracil or 4-ethoxy-2-keto-1,2-dihydropyrimidine with glycidol in a dimethylformamide medium in the presence of anhydrous potassium carbonate (cf. N. Ueda, T. Kawabata, K. Takemoto, L. Heterocyclic Chem., 1971, 8, 827).

Also known in the art is a process for producing N₁ -(3',5'-dihydroxypentyl-1)-uracil (cf. B. R. Baker, T. J. Shawan, J. Med. Chem., 1966, 9, 73) by condensing uracil with 1-chloro-3,5-diacetoxypentane, followed by hydrolysis of acetyl groups with butylamine.

None of said prior-art processes can be applied for the synthesis of other N₁ -dihydroxyalkyluracils.

It is an object of the present invention to provide a process for producing N₁ -(dihydroxyalkyl)-5-substituted uracil derivatives which would enable the production of all the compounds corresponding to the generic formula given hereinabove.

This object is accomplished by the process for producing N₁ -(dihydroxyalkyl)-5-substituted uracils of the formula: ##SPC5##

Wherein

R₁ is hydrogen, methyl, a trihalomethyl or a halogen,

R₂ is 1,4-hydroxybutyl-2, 1,4-dihydroxypentyl-2,2,5-dihydroxypentyl-1,

Which, according to the present invention, comprises reducing N₁ -(butyrolactone)uracils of the formula: ##SPC6##

Wherein R₁ is hydrogen, methyl, a trihalomethyl or a halogen, and A is ##SPC7##

With an alkali metal boron hydride in an aqueous or aquo-alcoholic solution at a temperature ranging from 15° to 50°C. The reaction of interaction of the components proceeds according to schemes I, II, III: ##SPC8##

The process for producing said N₁ -(dihydroxyalkyl)-uracils is performed in the following manner.

A suspension of a N₁ -(butyrolactone)-5-substituted uracil in water is gradually added, with stirring, to an aqueous or alcoholic solution of an alkali metal boron hydride such as sodium boron hydride at room temperature. 20-30 minutes after the addition of the total amount of the N₁ -(butyrolactone)-uracil, its complete dissolution in the reaction mixture is observed.

The reaction mixture is allowed to stand for 2-3 hours, whereafter it is acidified with acetic acid to pH = 5 decompose the excess of said boron hydride, passed through a column filled with a cationite "Amberlite-IR-120", and eluted with water. The eluate is passed through a column with an anionite "Dowex-3", eluted with water and then with a 0.5N aqueous ammonia solution.

The aqueous eluate, after evaporation, gives N₁ -(dihydroxyalkyl)-5-substituted uracil derivatives. The ammoniacal liquor contains a by-product of the reaction, viz. an ammonium salt of a corresponding hydroxy-acid.

For better understanding of the present invention, the following Examples illustrating the production of N₁ -(dihydroxyalkyl)-5-substituted uracil derivatives are given hereinbelow.

EXAMPLE 1: PRODUCTION OF N₁ -(1,4-DIHYDROXYBUTYL-2)-URACIL

To a solution of 0.8 g (0.022 mol) of sodium boron hydride in 40 ml of water there is added, under stirring, a suspension of 3 g (0.015 mol) of N₁ -(α-butyrolactone)uracil in 40 ml of water. The reaction mixture is stirred for 2-3 hours at room temperature. Then, the excess sodium boron hydride is decomposed with acetic acid, passed through a column with a cationite such as "Amberlite IR-120", and eluted with water. The eluate is passed through a column with "Dowex-3" anionite, eluted with water and then with a 0.5M ammonia solution. After evaporation, the aqueous eluate gives 1.7 g (57% of the theoretical amount) of N₁ -(1,4-dihydroxybutyl-2)uracil in the form of white crystals which are then recrystallized from ethanol. Melting point 108°-110°C.

UV-spectrum, pH = 2,λ_(max) 266(ε9.630); pH =12λ_(max) 265(ε7.100);

IR-spectrum 1,060 cm⁻ ¹ (.sup.→_(C-OH)), 3,300-3,450 cm⁻ ¹ ; (ν_(OH)) 1,680, 1,720 cm⁻ ¹ (ν_(CO)).

Analysis. Found, %: C, 48.25; H, 6.20; N, 14.12. C₈ H₁₂ N₂ O₄. Calculated, %: C, 47.99; H, 6.04; N, 13.99.

EXAMPLE 2: PRODUCTION OF N₁ -(1,4-DIHYDROXYBUTYL-2)-5-FLUOROURACIL

The reaction is conducted as described in Example 1. Using 3 g (0.014 mol) of N₁ -(α-butyrolactone)-5-fluorouracil and 0.8 g (0.022 mol) of sodium boron hydride, there is obtained 1 g (33% of the theoretical amount) of N₁ -(1,4-dihydroxybutyl-2)-5-fluorouracil in the form of a white crystalline substance. The desired product is recrystallized from ethanol. Melting point 181°-182°C.

UV-spectrum pH = 2λ_(max) 276(ε8,540), pH = 12λ_(max) 276(ε6,420)

IR-spectrum 1,670; 1,720 cm⁻ ¹ (ν_(CO)), 3,200-3,400 (ν_(OH)), 1,050 (ν_(C-OH)).

Analysis. Found, %: C, 44.49; H, 5.10; N, 12.93; F, 8.16. C₈ H₁₁ N₂ O₄ F. Calculated, %: C, 44.04; H, 5.08; N, 12.84; F, 8.70.

EXAMPLE 3: PRODUCTION OF N₁ -(1,4-DIHYDROXYPENTYL-2)-5-METHYLURACIL

The reaction is conducted as described in Example 1. Using 3.3 g (0.015 mol) of N₁ -(γ-methyl-α-butyrolactone)-5-methyluracil and 0.8 g (0.022 mol) of sodium boron hydride, there is obtained 1.2 g (53% of the theoretical amount) of N₁ -(1,4-dihydroxypentyl-2)-5-methyluracil which is then recrystallized from ethanol. Melting point 166°-168°C.

UV-spectrum pH = 2λ_(max) 273(ε9.200), pH = 12λ_(max) 273(ε7,100).

IR-spectrum 1,680; 1,700 cm⁻ ¹ (ν_(CO)); 3,230-3,420 cm⁻ ¹ (ν_(OH)); 1,050 cm⁻ ¹ (ν_(C-OH)).

Analysis. Found, %: C, 52.05; H, 7.28; N, 12.42. C₁₀ H₁₆ N₂ O₄. Calculated, %: C, 52.19; H, 7.02; N, 12.28.

EXAMPLE 4: PRODUCTION OF N₁ -(2,5-DIHYDROXYPENTYL-1)-5-TRIFLUOROMETHYLURACIL

The reaction is conducted as described in Example 1. Using 4.2 g (0.015 mol) of N₁ -(butyrolactone-γ-methylene)-5-trifluoromethyluracil and 0.8 g (0.022 mol) of sodium boron hydride, there is obtained 0.8 g (28% of the theoretical amount) of N₁ -(2,5-dihydroxypentyl-1)-5-trifluoromethyluracil. The product is recrystallized from ethanol. Melting point is 195°-197°C.

UV-spectrum pH = 2 λ_(max) 262(ε9.940) pH = 12λ_(max) 261(ε6.720);

IR-spectrum 1,680; 1,700 cm⁻ ¹ (ν_(CO)); 3,200-3,400 cm⁻ ¹ (ν_(OH)), 1,050; 1,090 cm⁻ ¹ (ν_(C-OH)).

Analysis. Found, %: C, 42.85; H, 4.60; N, 9.99; F, 19.73. C₁₀ H₁₃ N₂ O₄ F₃. Calculated, %: C, 42.55; H, 4.64; N, 9.79; F, 20.20. 

1. A process for producing N₁ -(dihydroxyalkyl)-5-substituted uracils of the formula: ##SPC9##where R₁ is selected from the group consisting of hydrogen, methyl, trifluoromethyl and fluorine; R₂ is selected from the group consisting of 1,4-dihydroxybutyl-2,1,4-dihydroxypentyl-2, and 2,5-dihydroxypentyl-1, comprising reducing N₁ -(butyrolactone) uracils of the formula: ##SPC10## wherein R₁ is selected from the group consisting of hydrogen, methyl, trifluoromethyl and fluorine; and A is selected from the group consisting of ##SPC11## with an alkali metal boron hydride in an aqueous or aqua-alcoholic solution at a temperature ranging from 15° to 50°C.
 2. A process according to claim 1 wherein R₁ is hydrogen and A is ##SPC12##
 3. A process according to claim 1 wherein R₁ is fluorine and A is ##SPC13##
 4. A process according to claim 1 wherein R₁ is methyl, and A is ##SPC14##
 5. A process according to claim 1 wherein R₁ is trifluoromethyl and A is ##SPC15## 